Process for the preparation of pregnanoic acid derivatives

ABSTRACT

Topical anti-inflammatory pregnanoic acid derivatives of the formula   WHEREIN -A-B- is -CH2-CH2-, -CH CH-, or -CCl CH-; X is a hydrogen atom, a halogen atom, or methyl; Y is a hydrogen atom or a halogen atom; Z is a hydroxy or a halogen atom having an atomic weight the same as or lower than Y; R1 is a hydrogen atom or methyl; and R2 is hydrocarbon, are produced in two steps by first converting a 21-hydroxy steroid of the formula   WHEREIN -A-B, X, Y, Z, and R1 have the values given above, into the corresponding 20-keto-21-aldehyde, or hydrate or hemiacetal thereof, with an alcohol in the presence of a copper (II) salt, and then converting the thus-produced steroid, with an oxidizing heavy metal oxide in the presence of an alcohol and cyanide ions, into the pregnanoic acid derivative.

United States Patent 1191 Laurent et al.

[ Apr. 1,1975

[ PROCESS FOR THE PREPARATION OF PREGNANOIC ACID DERIVATIVES [75]lnventors: Henry Laurent; Rudolf Wiechert,

both of Berlin, Germany [73] Assignee: Schering Aktiengesellschaft,Berlin and Bergkamen, Germany [22] Filed: Dec. 5, 1973 [21] Appl. No.:421,820

[30} Foreign Application Priority Data Dec. 6, 1972 Germany 2260303 [52]US. Cl. 260/397.l, 260/397.45 [51] Int. Cl. C070 167/18 58] Field ofSearch 260/397.l

Primary Examiner-Elbert L. Roberts 4Ir0rney, Agent, or FirmMillen,Raptes & White {57] ABSTRACT Topical anti-inflammatory pregnanoic acidderivatives of the formula wherein -A-B-- is CH CH CH=CH, or CCl=CH; Xis a hydrogen atom, a halogen atom, or methyl; Y is a hydrogen atom or ahalogen atom; Z is a hydroxy or a halogen atom having an atomic weightthe same as or lower than Y; R is a hydrogen atom or methyl; and R ishydrocarbon, are produced in two steps by first converting a 2 l-hydroxysteroid of the formula wherein A-B, X, Y, Z, and R have the values givenabove, into the corresponding 20-keto-2laldehyde, or hydrate orhemiacetal thereof, with an alcohol in the presence of a copper (ll)salt, and then converting the thus-produced steriod, with an oxidizingheavy metal oxide in the presence of an alcohol and cyanide ions, intothe pregnanoic acid derivative.

17 Claims, No Drawings 1 2 PROCESS FOR THE PREPARATION OF wherein A--B,X, Y, Z, R and R have the above- PREGNANOIC ACID DERIVATIVES indicatedmeanings and the 20-hydroxy group is in the aor B-position, and thenconverting these compounds by oxidation of the 20-hydroxy group intopregnanoic BACKGROUND OF THE INVENTION 5 acid derivatives of generalFormula I.

This invention relates to a process for the preparation Compared to theprocess described in German Pat. of pregnanoic acid derivatives of thegeneral Formula Application No. p 21 50 268.1, the two-step process of Ithis invention represents a considerable advance in the art, inasmuch asit is possible with the aid thereof to COOR l0 surprisingly obtain in anessentially shorter period of time substantially higher yields.According to the C=O method of the present invention, a reaction time ofmaximally two hours is normally required for each of R1 the two reactionsteps, if the reactions are conducted at room temperature. In contrastthereto, several days 3 I are necessary for the first reaction stepalone of the process of the above-identified patent applications, if

/ conducted at room temperature. With the aid of the process of thisinvention, yields of between 60% and 75% of theory are normallyobtained, considering both reaction steps; even in unfavorable cases,yields are approximately 50% of theory. In contrast thereto, over-allwherein A i5 2- 0F yields obtained in the process of Ser. No. 284,710and C X is a y g atom, a halogen atom, German Pat. Application No. p 2150 268.1, considermethyli Y is hydrogen mom or a halogen atom; Z is 25ing both stages together, are normally 10% to of a hydroxy or a halogenatom having an atomic weight h the same as or lower than Y; R, is ahydrogen atom or methyl; and R is hydrocarbon. RY F THE INVENTION ThePregnanoic acid derivatives of general Formula According to thisinvention, a 2l-hydroxy steroid of I have been described in UnitedStates Application 30 the general Formula II is converted, by reactionwith an 384-710 filed g 1972- the disclosure of alcohol in the presenceof a copper (II) salt, into a stewhich is incorporated by reference, andGerman Pat. mid aldehyde f the genera] Formula IV Application p 21268.1. As also disclosed in these patent applications, these pregnanoicacid derivatives possess topical antiinflammatory activity and can be 35produced from 2l-hydroxy steroid of the general For- CH0 mula II cn onIV C=O Z t 5 x O herein AB X Y Z and R have the same wherein A-B, X, Y,Z, and R, have the values W I l given for Formula I, by converting thelatter into pregmedpmgs as set forth Formula hydrate f i d fives, of theeneml Formula m 5s hemiacetal thereof, which is then oxidized with an0X1- g dizing heavy metal oxide in the presence of an alcohol (30011 andcyanide ions into a pregnanoic acid derivative.

H AM OH DETAILED DISCUSSION Z Of the starting compounds of Formula I,preferred R1 sub-classes are those wherein:

' I 11 la. R is alkyl of l-l2 carbon atoms, preferably 1-8 carbon atoms;lb. X is fluoro, especially those of la; lc. Y is hydrogen, especiallythose of la and lb;

Id. Z is hydroxy, especially those of la, lb and lc; le. AB isCl-I=CI-l, especially those of la,

lb, lo and Id;

If. R is methyl, especially those of la, lb, lc, Id and When X, Y or Zis a halogen atom, it preferably is fluo'rine or chlorine.

Because activity resides in the pregnanoic acid steroidal structure,COOR can represent any ester group.

For example, in the process of this invention, Rgcan be any hydrocarbongroup derived from a reaction alcohol of l-l6, preferably l-l2, carbonatoms. The hydrocarbon group can be aliphatic, e.g., alkyl, orcycloaliphatic, preferably monocyclic or aralkyl.

Examples of aliphatic R groups are straight and branched chain alkyl ofl-l2, preferably l- 8, more preferably 1-4 carbon atoms, e.g., methyl,ethyl, propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl, amyl.isoamyl, tert.-amyl,' hexyl, heptyl, octyl, decyl, dodecyl, tetradecyland hexadecyl.

Examples of cycloalkyl are those containing 3-12, preferably 5 or 6 ringcarbon atoms, e.g.,cyclopropyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cyclopentenyl, cyclopentadienyl and p-dicyclohexyl.

Examples of aryl are mono and dicyclic of up to 12 carbon atoms, e.g.,phenyl, a-naphthyl and B-naphthyl and p-diphenyl.

Examples of alkaryl are tolyl, xylyl, ethylphenyl and sym-diethylphenyl.Examples of aralkyl are benzyl, phenylethyl and a-phenylpropyl anddiphenylmethyl.

It will be apparent to those skilled in the art that equivalents ofunsubstituted R hydrocarbon groups are hydrocarbon groups bearing 1, 2,3 or more simple substituents, preferably one, since such substituentsordinarily do not affect the overall activity of the parent pregnanoicacid. Examples of such simple substituents are halo, e.g., Cl or F, N0amido, lower-alkoxy, i.e., containing l-4 carbon atoms, e.g., methoxy,ethoxy, propoxy, butoxy and tert.-butoxy.

The process of this invention is a two-stage procedure. In the firststage, the 2l-hydroxy steroids of general Formula II are converted withalcohols, in the presence of copper (ll) salts, to the steroid aldehydesof general Formula IV.

Suitable copper (ll) salts for the first reaction are water solublesalts of inorganic or organic acids, e.g., copper (ll) inorganic mineralacid salts or preferably salts of lower carboxylic acids; copper (ll)salts ofinorganic acids can also be used. Suitable copper (ll) saltsinclude but are not limited to: copper (ll) formate, copper (1])acetate, copper (ll) propionate or copper (ll) butyrate.

Alcohols usable in this first reaction step are alcohols of the generalformula R OH, wherein R has the same meanings as in Formula 1.Especially preferred alcohols are lower and intermediate, primary orsecondary aliphatic alcohols having l-8 carbon atoms in the alcoholresidue. Suitable such alcohols include but are not limited to methanol,ethanol, propanol, isopropanol, butanol, isobutanol, see-butanol, amylalcohol, isoamy] alcohol, hexanol, heptanol or octanol. Excess alcoholcan also serve simultaneously as the reaction solvent, although it is ofcourse also possible to admix inert solvents to the reaction mixture inaddition to the alcohols. Suitable inert solvents are known in the artand include but are not limited to hydrocarbons, e.g., benzene,cyclohexane or toluene; chlorinated hydrocarbons, e.g., methylenechloride, chloroform or tetrachloroethane; ethers, e.g., diethyl ether,diisopropyl ether, glycol dimethyl ether, tetrahydrofuran or dioxane;dipolar aprotic solvents, e.g., dimethylformamide, N-methyl-acetamide orN-methylpyrrolidone; etc.

The first reaction step is preferably accomplished at a reactiontemperature of 0C to C. The reaction time required for the firstreaction step is dependent on the structure of the 2l-hydroxy steroidemployed and on the reaction temperature, but is generally 5-120minutes. The optimum reaction period can be determined withoutdifficulty foreach individual case by withdrawing aliquots from thereaction mixture at certain time intervals and examining these samplesby means of thin-layer chromatography. The optimum reaction time interms of yield is of course reached when the 2 l-hydroxy steroid used asthe starting material has been completely converted.

Depending on the selection of the specific reaction conditions and onwhether aqueous or anhydrous alcohols are utilized for the reaction, thefree steroid aldehydes of general Formula IV or the correspondinghydrates, hemiacetals or mixtures thereof are formed during thisreaction. The nature of the resultant product is in this aspectunimportant with respect to the subsequent reactions.

The conversion of the steroid aldehydes of general Formula lV into thepregnanoic acid derivatives of general Formula I can in principle beaccomplished with the aid of a great variety of oxidizing agents, as hasbeen demonstrated by our experiments.

For example, it is possible to convert the steroid aldehydes to thepregnanoic acid derivatives in the presence of acids with alcohols andorganic oxidizing agents, such as 5,6-dichloro-2,S-dicyanobenzoquinoneor triphenyltetrazolium chloride. However, this method has thedisadvantages that the oxidizing agents employed are very expensive, andthat the subsequent purification of the reaction products iscomplicated.

It is also possible to oxidize the steroid aldehydes with oxidizingmetallic oxides or metallic salts, such as manganese oxide, silveroxide, chromic acid, permanganate and similar compounds, in the presenceof alcohols and optionally of acids. These reactions, however, takeplace relatively slowly, and considerable proportions of undesiredby-products are formed in addition to the pregnanoic acid derivatives.

It is likewise possible to react the steroid aldehydes with atmosphericoxygen in the presence of alcohols and of cyanide ions. This reaction,though,,likewise takes place rather gradually, and undesired byproductsare also produced to a considerable extent.

In order to obtain a rapid reaction and high yields, it is advantageousto effect the second reaction step of the process of this invention withoxidizing heavy metal oxides in the presence of alcohols and of cyanideions. The second process step can be accomplished with the use of thesame alcohols and solvents as the first reaction step.

For the second reaction ,step, suitable heavy metal oxides are those ofGroups la, lIa, lVa, Va, Vlb and Vllb in the lower half ofthe PeriodicTable having an oxidation potential of at least +0.50; suitable such0xides include but are not limited to silver oxide,iead( IV) oxide,minium, vanadium (V) oxide, manganeseflv) oxide or chromium(VI) oxide(the latter compound only if the steroid aldehydes do not have an llB-hydroxy oxidizable group). The reaction is conducted preferably byusing 0.5 g. to 50 g. and especially 1 g. to 10 g. of heavy metal oxideper gram of steroid aldehyde. The catalyst employed for this reactionstep is cyanide ions. Reagents yielding cyanide ions are preferablyalkali metal cyanides, e.g., sodium or potassium cyanide. Preferably,0.01 moles and particularly 0.1 1 mole of cyanide is used per mole ofsteroid a1dehyde. 1f alkali cyanides are utilized as the reagentsyielding cyanide ions, the reaction is suitably con ducted by adding tothe reaction mixture an alkali neutralizing amount of acid, e.g.,mineral acid such as sulfuric acid, phosphoric acid or hydrogenchloride; sulfonic acid such as p-toluenesulfonic acid; or carboxylicacid such as formic acid or acetic acid to maintain the pH at about 2.0to 6.0.

The reaction is suitably conducted at a reaction temperature of betweenC and +100C and preferably at a reaction temperature of between 0 C and+50 C.

The duration of the reaction is dependent on the reaction temperatureand the selection of the reactants; on the average, this period is 15minutes to 120 minutes. In the individual case, the optimum reactiontime can be readily determined in the same manner as for the firstreaction step.

It is surprising to a person skilled in the art that the steroidaldehydes of general Formula IV can be converted rapidly and with theproduction of high yields into the pregnanoic acid derivatives ofgeneral Formula 1 with the use of oxidizing heavy metal oxides in thepresence of cyanide ions and alcohols because steroid aldehydes of thegeneral formula IV are only converted in low yields to pregnanoic acidderivatives of the general formula 1 when oxidized with heavy metaloxides in alcoholic solution in the absence of cyanide ions.

The following examples serve to explain the process of the presentinvention.

Without further elaboration, it is believed that one skilled in the artcan. using the-preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative and not limitative ofthe remainder of the disclosure in any way whatsoever. 1n the followingExamples, the temperatures are set forth uncorrected in degrees Celsius;unless otherwise indicated, all parts and percentages are by weight. Thevalues obtained in elemental analyses are within commonly acceptedlimits of error.

EXAMPLE 1 21-al as a crude product.

b. The thus-obtained product is dissolved in 50 ml. of butanol, and thesolution is stirred for minutes at room temperature after adding 165 mg.of potassium cyanide, 1.0 ml. of acetic acid, and 5 g. of manganese(lV)oxide. The manganese(lV) oxide is removed by filtration, the filtrate isdiluted with methylene chloride, washed with water, the organic phase isdried over sodium sulfate, and evaporated to dryness under vacuum. Theresidue is chromatographed on silica gel. With 12l5% acetone-hexane, 840mg. of a l crude product is eluted which yields, after recrystallization from acetone-hexane, 735 mg. of 6a-fluoro-1 1B- hydroxy-3,20-dioxo-loa-methyl-l,4-pregnadien-21- oic acid butyl ester; m.p. 195C.

[01],, +134 (chloroform).

EXAMPLE 2 EXAMPLE 3 Under the conditions set forth in Example 1(a), 1.0g. of 6a-fluoro-l 1,8,21-dihydroxy-l6a-methyl-5- pregnene-3,20-dione isoxidized to the oa-fluoro-l 1B- hydroxy-3,20-dioxo- 16a-methyl-4-pregnen-2 l-al. The thus-obtained product is converted,under the conditions described in Example 1(b),-into the butyl ester of6a-fluoro-1 ll3-hydroxy-3,20-dioxol 6a-methyl-4- pregnen-Zl-oic acid.Yield: 596 mg.; m.p. 192 C.

[01],, (chloroform).

EXAMPLE 4 1.0 g. of6a,9-difluoro-l1,8,21-dihydroxy-l6amethyl-l,4-pregnadiene-3,ZO-dione isconverted, under the conditions set forth in Example 1, into the butylester of 6a,9-difluoro-llB-hydroxy-3,20-di0xoloa-methyl-1,4-pregnadien-2l-oic acid. Yield: 752mg; m.p. 194 C.

[04],, +l22 (chloroform).

EXAMPLE 5 methyl-1,4-pregnadien-21-al is'converted in isopropanol, underthe conditions described in Example 1(b), into the isopropyl ester ofoa-fluoro-l 1fi-hydroxy-3,20- dioxo-loa-methyl-l,4-pregnadien-2l-oicacid. Yield: 649 mg.; m.p. 225 C.

[01],, +134 (chloroform).

EXAMPLE 6 Under the conditions set forth in Example 1(a), 1.0 g. of6a-flu0ro-9-chloro-l1,8,21-dihydroxy-l6amethy11,4-pregnadiene-3,20-dione is oxidized to the2 1 -aldehyde, and the latter is converted, under the conditionsindicated in Example 1(b) but in methanol with silver(l) oxide, into themethyl ester of 6a-fluoro-9- chloro-l lB-hydroxy-3,20-dioxo- 1oa-methyl- 1 ,4- pregnadien21-oic acid. Yield: 605 mg.; m.p. 225 C.

[011 +153 (dioxane).

I EXAMPLE 7 Under the conditions described in Example 1(a), 750 mg. of601,11B-difluoro-9-chloro-2l-hydroxy-l6amethyl-l,4-pregnadiene-3,20-dione isoxidized to the aldehyde, and the latter is converted, under theconditions set forth in Example 1(b), but in methanol with vanadium(V)oxide, into the methyl ester of 6a,l1B-

7 difluoro-9-chloro-3,20-dioxo-16a-methyl-l ,4-pregnadien-2l-oic acid.Yield: 510 mg.; mp. 240 C.

[01],, +l38 (chloroform).

EXAMPLE 8 EXAMPLE 9 Under the conditions set forth in Example 1(a), 550mg. of 9-fluoro-l 13,2 l-dihydroxy-loa-methyl-l,4-pregnadiene-3,20-dione is oxidized to the 2l-aldehyde, and the latter isconverted, under the conditions described in Example [(12), in methanolinto the methyl ester of 9-fluoro-llB-hydroxy-3,20-dioxo-l6a-methyll,4-pregnadien-2l-oic acid. Yield: 418mg; mp. 215 C 111 +l40 (chloroform).

EXAMPLE 10 Under the conditions indicated in Example 1(a), 750 mg. of l13,2l-dihydroxy-l,4-pregnadiene-3,20-dione is oxidized to the2l-aldehyde, and the latter is converted, under the conditions set forthin Example l(b), in ethanol into the ethyl ester of llB-hydroxy-3,20-dioxo-l,4-pregnadien-2 l-oic acid. Yield: 382 mg; mp. 190 C.

EXAMPLE ll Under the conditions indicated in Example l, 1.0 g. of l IB,2l-dihydroxy- 1 6a-methyll ,4-pregnadiene- 3.20-dione is converted intothe butyl ester of HB- hydroxy-l 6a-methyl-3,20-dioxol 6a-methyl-l,4-pregnadien-Zl-oic acid. Yield: 670 mg.; mp. 149 C.

[al +l53 (chloroform).

The preceding examples can be repeated with similar success bysubstituting the generically and specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof. can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:

l. A process for the production of pregnanoic acid derivatives of theformula wherein AB is CH CH CH=CH-, or CCl=CH; X is hydrogen, halogen ormethyl; Y is hydrogen or halogen; Z is hydroxy or a halogen having anatomic weight the same as or lower than Y; R, is hydrogen atom ormethyl; and R is alkyl of 1-12 carbon atoms, cycloalkyl of 3-12 ringcarbon atoms, mono or dicyclic aryl of up to 12 ring carbon atoms,phenylalkyl or alkylphenyl, which comprises i. reacting a 2l-hydroxysteroid of the formula wherein A-B-, X, Y, Z, and R, have the valuesgiven above, with an alcohol of the formula R OH wherein R has thevalues given above, in the presence,

ofa water soluble copper(ll) salt of an acid to form the correspondingsteroid aldehydes or hydrates or hemiacetals thereof, of the formulawherein AB, X, Y, Z, and R have the aboveindicated values, and 7 ii.oxidizing said aldehyde. hydrate or hemiacetal with an oxidizing oxideof a metal of Groups la, lla, lVa, Vlb and Vllb in the lower half of thePeriodic Table having an oxidation potential of at least 0.50 in thepresence of an alcohol and as catalyst for the oxidation, an alkalimetal cyanide, to form the corresponding pregnanoic acid derivative. 2.A process according to claim 1, wherein R is alkyl or 1-8 carbon atoms.-

3. A process according to claim 1, wherein the copper(ll) salt is thesalt of a lower carboxylic acid.

4. A process according to claim 3, wherein the salt is copper(ll)formate, acetate, propionate or butyrate.

5. A process according to claim 1, wherein the alcov hol R- OH is aprimary or secondary aliphatic alcohol.

6. A process according to claim 1, wherein the oxidizing oxide isselected from the group consisting of silver oxide, lead(lV) oxide.minium, vanadium(V) oxide, manganese(lV) oxide and chromium(Vl) oxide.

7. A process according to claim 1, wherein the cyanide is sodium orpotassium cyanide.

8. A process according to claim 1, wherein the reaction medium furthercomprises an alkali-neutralizing amount of acid.

9. A process according to claim 8, wherein the copper(ll) acid salt isthe salt of a lower carboxylic acid and wherein the alcohol R- ,OH is aprimary or secondary aliphatic alcohol.

10. A process for the production of pregnanoic acid derivatives of theformula coon in the presence of an alcohol and as catalyst for the oxi-I dation, an alkali metal cyanide to form the corresponding pregnanoicacid derivative.

11. A process according to claim 8 wherein the copper(ll) salt iscopper(ll) formate, acetate, propionate or butyrate, wherein the alcoholR Ol-l is a primary or secondary aliphatic alcohol, wherein theoxidizing oxide is selected from the group consisting of silver oxide,lead(lV) oxide, minium, vanadium(V) oxide, manganese(lV) oxide andchromium(Vl) oxide, and wherein the cyanide is sodium or potassiumcyanide.

12. A process according to claim 10 wherein the salt is copper(ll)formate, acetate, propionate or butyrate.

13. A process according to claim 10 wherein the alcohol is a primary orsecondary aliphatic alcohol.

14. A process according to claim 10, wherein the oxidizing oxide isselected from the group consisting of silver oxide, lead(lV) oxide,minium, vanadium(V) oxide, manganese(lV) oxide and chromium (VI) oxide.

15. A process according to claim 10 wherein the cyanide is sodium orpotassium.

16. A process according to claim 10, wherein the reaction medium furthercomprises an alkali-neutralizing amount of acid.

17. A process according to claim 10, wherein the copper(ll) salt iscopper(ll) formate, acetate, propionate or butyrate, wherein the alcoholR OH is a primary or secondary aliphatic alcohol, wherein the oxidizingoxide is selected from the group consisting of silver oxide, lead(lV)oxide, minium, vanadium(V) ox ide, manganese(lV) oxide and chromium(Vl)oxide, and wherein the cyanide is sodium or potassium cya-

1. A PROCESS FOR THE PRODUCTION OF PREGNANOIC ACID DERIVATIVES OF THEFORMULA
 2. A process according to claim 1, wherein R2 is alkyl or 1-8carbon atoms.
 3. A process according to claim 1, wherein the copper(II)salt is the salt of a lower carboxylic acid.
 4. A process according toclaim 3, wherein the salt is copper(II) formate, acetate, propionate orbutyrate.
 5. A process according to claim 1, wherein the alcohol R2OH isa primary or secondary aliphatic alcohol.
 6. A process according toclaim 1, wherein the oxidizing oxide is selected from the groupconsisting of silver oxide, lead(IV) oxide, minium, vanadium(V) oxide,manganese(IV) oxide and chromium(VI) oxide.
 7. A process according toclaim 1, wherein the cyanide is sodium or potassium cyanide.
 8. Aprocess according to claim 1, wherein the reaction medium furthercomprises an alkali-neutralizing amount of acid.
 9. A process accordingto claim 8, wherein the copper(II) acid salt is the salt of a lowercarboxylic acid and wherein the alcohol R2OH is a primary or secondaryaliphatic alcohol.
 10. A process for the production of pregnanoic acidderivatives of the formula
 11. A process according to claim 8 whereinthe copper(II) salt is copper(II) formate, acetate, propionate orbutyrate, wherein the alcohol R2OH is a primary or secondary aliphaticalcohol, wherein the oxidizing oxide is selected from the groupconsisting of silver oxide, lead(IV) oxide, minium, vanadium(V) oxide,manganese(IV) oxide and chromium(VI) oxide, and wherein the cyanide issodium or potassium cyanide.
 12. A process according to claim 10 whereinthe salt is copper(II) formate, acetate, propionate or butyrate.
 13. Aprocess according to claim 10 wherein the alcohol is a primary orsecondary aliphatic alcohol.
 14. A process according to claim 10,wherein the oxidizing oxide is selected from the group consisting ofsilver oxide, lead(IV) oxide, minium, vanadium(V) oxide, manganese(IV)oxide and chromium (VI) oxide.
 15. A process according to claim 10wherein the cyanide is sodium or potassium.
 16. A process according toclaim 10, wherein the reaction medium further comprises analkali-neutralizing amount of acid.
 17. A process according to claim 10,wherein the copper(II) salt is copper(II) formate, acetate, propionateor butyrate, wherein the alcohol R2OH is a primary or secondaryaliphatic alcohol, wherein the oxidizing oxide is selected from thegroup consisting of silver oxide, lead(IV) oxide, minium, vanadium(V)oxide, manganese(IV) oxide and chromium(VI) oxide, and wherein thecyanide is sodium or potassium cyanide.